Project Summary We propose to apply our new panel of structure-based inhibitors of tau aggregation, developed against polymorphic structures of aggregated tau, to detect the spectrum of tau polymorphs that are found in dementias ranging from non-progressing MCI, to rapidly-progressing AD and numerous related tauopathies. The goal is to determine the prevalence, and consequences of particular polymorphs in the patient population, which has remained ill-defined despite the new structures of tau fibrils. In Aim 1 we employ inhibitor profiling to discover and classify tau polymorphs from autopsied brain tissue samples. Aim 2 builds upon the first by using different patient-derived polymorphs discovered in Aim 1 to seed aggregation in a transgenic tau mouse model. Seeded mouse lines established in Aim 2 will allow us to uncover the pathological consequences of different polymorphs on the progression of tau pathology, and the opportunity to test the efficacy of our panel of inhibitors against disease-relevant polymorphs of tau in an in vivo model. Additionally we will develop translatable ways of delivering our inhibitors of tau aggregation to the brain. Aim 3 develops strain-specific imaging agents to detect and profile amyloid polymorphs that are present in the brain of living organisms. We concentrate our effort on MRI imaging agents because MR does not use ionizing radiation, unlike PET. Thus, MRI agents developed by us could be safely used repeatedly for longitudinal studies for both diagnostics, and for following the evolution of polymorphs in patients over time. As an added benefit, MRI has higher spatial resolution than PET, which could potentially allow our MR imaging agents to be used to delineate tau pathology in substructures of the brain. Our team of researchers has expertise in structural biology of amyloid polymorphs, mouse models of neurodegeneration, technological methodologies for delivering therapeutics across the blood-brain-barrier, and MRI imaging of brain diseases. If successful, our project will result in a set of strain-specific MRI imaging compounds for each of the polymorphic varieties of tau in AD, which could be used in living patients to guide the diagnosis of AD and tauopathies, and to inform clinicians on which tau inhibitors of our panel would work best for given AD patients. Additionally, these tools will be useful for tracking the evolution of polymorphs in patients as they emerge over time.